The present invention relates to novel cyclic peptides having antagonistic activity on endothelin receptors and antagonistic activity on NK2 receptors. These cyclic peptides are useful as prophylactic and therapeutic drugs for hypertension, cardiac or cerebral circulatory diseases, renal diseases and asthma, anti-inflammatory drugs, antarthritics and the like. The present invention further relates to the use thereof.
Endothelin (ET) is a vasoconstrictive peptide composed of 21 amino acid residues. Endothelin was isolated from the culture supernatant of the endothelial cells of porcine aortas. Its structure was determined by M. Yanagisawa et al. in 1988 (M. Yanagisawa et al., Nature 332, 411-412 (1988)). More recently, the research on genes coding for endothelin revealed the presence of peptides similar to endothelin in structure. These peptides are named endothelin-1 (ET-1), endothelin-2 (ET-2) and endothelin-3 (ET-3), respectively. Their structures are as follows:
______________________________________ H--Cys--A1--Cys--A2--A3--A4--A5--Asp--Lys--Glu--Cys-- Val--Tyr--A6--Cys--His--Leu--Asp--Ile--Ile--Trp--OH A1 A2 A3 A4 A5 A6 ______________________________________ ET-1 Ser Ser Ser Leu Met Phe ET-2 Ser Ser Ser Trp Leu Phe ET-3 Thr Phe Thr Tyr Lys Tyr ______________________________________
All of the amino acids constituting ET-1, ET-2 and ET-3 take the L-form (Inoue et al., Proc. Natl. Acad. Sci. U.S.A. 86, 2863-2867 (1989)).
The above-mentioned peptides of the endothelin family exist in vivo and have vasopressor activity. For this reason, these peptides are anticipated to be intrinsic factors responsible for the control of circulatory systems, and deduced to be related to hypertension, cardiac or cerebral circulatory diseases such as cardiac infarction and renal diseases such as acute renal insufficiency. In addition, these peptides also have bronchial smooth muscle constrictor activity, and therefore deduced to be related to asthma.
If antagonists to the receptors of the above-mentioned peptides of the endothelin family are obtained, they are not only considered to be useful for elucidation of the functional mechanism of these peptides, but also likely to be used as effective therapeutic drugs for the above-mentioned diseases. We already filed applications for patents with respect to fermentation product-derived cyclic pentapeptides having the antagonistic activity on the endothelin receptors (Japanese Patent Application Nos. 2-413828/1990 and 3-126160/1991). It is therefore an object of the present invention to provide novel peptides which are effective similarly or more than the peptides previously filed.